Tissue ischemia, whether of the heart or other organs, is a major clinical challenge. It has been widely hoped that angiogenic cytokines, such as vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) family members could grow new blood vessels to benefit such patients but success has not yet been realized. VEGF-A164, VEGF-A120 and PIGF generate a vascular response that is highly abnormal and that closely mimics that of pathological angiogenesis (e.g., healing myocardial infarcts). Several types of abnormal new blood vessels form: "mother" vessels and "daughter" vessels including glomeruloid bodies (GB), capillaries and vascular malformations and these are accompanied by vascular permeability, edema and clotting. However, the molecular mechanisms by which these vessels form is not yet understood. Also, to provide a useful blood supply, it is likely that more normal vessels are required. The first goal of this application is to elucidate the molecular mechanisms by which primary angiogenic cytokines such as VEGF-A164, VEGF-A120 and PIGF induce the abnormal new blood vessels that are typical of pathological angiogenesis. The second goal is to induce more normal vessels; this will be accomplished by supplementation of VEGF-A isomers with additional, secondary cytokines that have been suggested from studies of vasculogenesis and physiological angiogenesis, processes that lead to the formation of the normal vasculature. The studies we propose can provide a solid basis for translation to the bedside. Specific aims are as follows: Aim 1. Elucidate the mechanisms by which VEGF-A164, VEGF-A120 and PIGF induce mother vessels. Aim 2. Elucidate the mechanisms by which mother vessels evolve into daughter vessels. Aim 3. Generate normal blood vessels with mixtures of primary and secondary cytokines.